Erythromyacin antibiotic product, use and formulation thereof

ABSTRACT

An antibiotic product, in particular an erythromyacin, is comprised of at least three dosages forms, each of which has a different release profile, with the C max  for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a C max  at different times.

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 09/792,092, filed on Feb. 22, 2000, which is acontinuation-in-part of U.S. application Ser. No. 09/687,229, filed onOct. 13, 2000, and also claims the priority of U.S. ProvisionalApplication Serial No. 60/184,546 filed on Feb. 24, 2000.

[0002] This invention relates to an antibiotic product, as well as theuse and formulation thereof. The invention further relates to anerythromyacin antibiotic product, in particular an erythromyacinderivative or a macrolide or a ketolite (including derivatives thereofsuch as salts, esters, etc.); in particular Clarithromycin.

[0003] A wide variety of antibiotics have been used, and will be used,in order to combat bacterial infection. In general, such antibiotics canbe administered by a repeated dosing of immediate release dosage forms,which results in poor compliance or as a controlled release formulation(slow release) at higher administered doses. The present invention isdirected to providing for an improved antibiotic product.

[0004] In accordance with one aspect of the present invention, there isprovided an antibiotic pharmaceutical product which is comprised of atleast two, preferably at least three, antibiotic dosage forms. Suchdosage forms are formulated so that each of the dosage forms has adifferent release profile.

[0005] In a particularly preferred embodiment, there are at least two,preferably at least three dosage forms, each of which has a differentrelease profile and the release profile of each of the dosage forms issuch that the dosage forms each start release of the antibioticcontained therein at different times after administration of theantibiotic product.

[0006] Thus, in accordance with an aspect of the present invention,there is provided a single or unitary antibiotic product that hascontained therein at least two, preferably at least three antibioticdosage forms, each of which has a different release profile, whereby theantibiotic contained in each of such dosage forms is released atdifferent times.

[0007] In accordance with a further aspect of the invention, theantibiotic product may be comprised of at least four different dosageforms, each of which starts to release the antibiotic contained thereinat different times after administration of the antibiotic product.

[0008] The antibiotic product generally does not include more than fivedosage forms with different release times.

[0009] In accordance with a preferred embodiment, the antibiotic producthas an overall release profile such that when administered the maximumserum concentration of the total antibiotic released from the product isreached in less than twelve hours, preferably in less than eleven hours.In an embodiment, the maximum serum concentration of the totalantibiotic released from the antibiotic product is achieved no earlierthan four hours after administration.

[0010] In accordance with one preferred embodiment of the invention,there are at least three dosage forms. One of the at least three dosageforms is an immediate release dosage form whereby initiation of releaseof the antibiotic therefrom is not substantially delayed afteradministration of the antibiotic product. The second and third of the atleast three dosage forms is a delayed dosage form (which may be a pHsensitive or a non-pH sensitive delayed dosage form, depending on thetype of antibiotic product), whereby the antibiotic released therefromis delayed until after initiation of release of the antibiotic from theimmediate release dosage form. More particularly, the antibiotic releasefrom the second of the at least two dosage forms achieves a C_(max)(maximum serum concentration in the serum) at a time after theantibiotic released from the first of the at least three dosage formsachieves a C_(max) in the serum, and the antibiotic released from thethird dosage form achieves a C_(max) in the serum after the C_(max) ofantibiotic released from the second dosage form.

[0011] In one embodiment, the second of the at least two dosage formsinitiates release of the antibiotic contained therein at least one hourafter the first dosage form, with the initiation of the releasetherefrom generally occurring no more than six hours after initiation ofrelease of antibiotic from the first dosage form of the at least threedosage forms.

[0012] In general, the immediate release dosage form produces a C_(max)for the antibiotic released therefrom within from about 0.5 to about 2hours, with the second dosage form of the at least three dosage formsproducing a C_(max) for the antibiotic released therefrom in no morethan about four hours. In general, the C_(max) for such second dosageform is achieved no earlier than two hours after administration of theantibiotic product; however, it is possible within the scope of theinvention to achieve C_(max) in a shorter period of time.

[0013] As hereinabove indicated, the antibiotic product may contain atleast three or at least four or more different dosage forms. Forexample, if the antibiotic product includes a third dosage form, theantibiotic released therefrom reaches a C_(max) at a time later than theC_(max) is achieved for the antibiotic released from each of the firstand second dosage forms. In a preferred embodiment, release ofantibiotic from the third dosage form is started after initiation ofrelease of antibiotic from both the first dosage form and the seconddosage form. In one embodiment, C_(max) for antibiotic release from thethird dosage form is achieved within eight hours.

[0014] In another embodiment, the antibiotic product contains at leastfour dosage forms, with each of the at least four dosage forms havingdifferent release profiles, whereby the antibiotic release from each ofthe at least four different dosage forms achieves a C_(max) at adifferent time.

[0015] As hereinabove indicated, in a preferred embodiment, irrespectiveof whether the antibiotic contains at least two or at least three or atleast four different dosage forms each with a different release profile,C_(max) for all the antibiotic released from the antibiotic product isachieved in less than twelve hours, and more generally is achieved inless than eleven hours.

[0016] In a preferred embodiment, the antibiotic product is a once a dayproduct, whereby after administration of the antibiotic product, nofurther product is administered during the day; i.e., the preferredregimen is that the product is administered only once over a twenty-fourhour period. Thus, in accordance with the present invention, there is asingle administration of an antibiotic product with the antibiotic beingreleased in a manner such that overall antibiotic release is effectedwith different release profiles in a manner such that the overallC_(max) for the antibiotic product is reached in less than twelve hours.The term single administration means that the total antibioticadministered over a twenty-four hour period is administered at the sametime, which can be a single tablet or capsule or two or more thereof,provided that they are administered at essentially the same time.

[0017] Applicant has found that a single dosage antibiotic productcomprised of at least three antibiotic dosage forms each having adifferent release profile is an improvement over a single dosageantibiotic product comprised of an antibiotic dosage form having asingle release profile. Each of the dosage forms of antibiotic in apharmaceutically acceptable carrier may have one or more antibiotics andeach of the dosage forms may have the same antibiotic or differentantibiotics.

[0018] It is to be understood that when it is disclosed herein that adosage form initiates release after another dosage form, suchterminology means that the dosage form is designed and is intended toproduce such later initiated release. It is known in the art, however,notwithstanding such design and intent, some “leakage” of antibiotic mayoccur. Such “leakage” is not “release” as used herein.

[0019] If at least four dosage forms are used, the fourth of the atleast four dosage form may be a sustained release dosage form or adelayed release dosage form. If the fourth dosage form is a sustainedrelease dosage form, even though C_(max) of the fourth dosage form ofthe at least four dosage forms is reached after the C_(max) of each ofthe other dosage forms is reached, antibiotic release from such fourthdosage form may be initiated prior to or after release from the secondor third dosage form.

[0020] The antibiotic product of the present invention, as hereinabovedescribed, may be formulated for administration by a variety of routesof administration. For example, the antibiotic product may be formulatedin a way that is suitable for topical administration; administration inthe eye or the ear; rectal or vaginal administration; as nose drops; byinhalation; as an injectable; or for oral administration. In a preferredembodiment, the antibiotic product is formulated in a manner such thatit is suitable for oral administration.

[0021] For example, in formulating the antibiotic product for topicaladministration, such as by application to the skin, the at least twodifferent dosage forms, each of which contains an antibiotic, may beformulated for topical administration by including such dosage forms inan oil-in-water emulsion, or a water-in-oil emulsion. In such aformulation, the immediate release dosage form is in the continuousphase, and the delayed release dosage form is in a discontinuous phase.The formulation may also be produced in a manner for delivery of threedosage forms as hereinabove described. For example, there may beprovided an oil-in-water-in-oil emulsion, with oil being a continuousphase that contains the immediate release component, water dispersed inthe oil containing a first delayed release dosage form, and oildispersed in the water containing a third delayed release dosage form.

[0022] It is also within the scope of the invention to provide anantibiotic product in the form of a patch, which includes antibioticdosage forms having different release profiles, as hereinabovedescribed.

[0023] In addition, the antibiotic product may be formulated for use inthe eye or ear or nose, for example, as a liquid emulsion. For example,the dosage form may be coated with a hydrophobic polymer whereby adosage form is in the oil phase of the emulsion, and a dosage form maybe coated with hydrophilic polymer, whereby a dosage form is in thewater phase of the emulsion.

[0024] Furthermore, the antibiotic product with at least three differentdosage forms with different release profiles may be formulated forrectal or vaginal administration, as known in the art. This may take theform of a cream or emulsion, or other dissolvable dosage form similar tothose used for topical administration.

[0025] As a further embodiment, the antibiotic product may be formulatedfor use in inhalation therapy by coating the particles and micronizingthe particles for inhalation.

[0026] In a preferred embodiment, the antibiotic product is formulatedin a manner suitable for oral administration. Thus, for example, fororal administration, each of the dosage forms may be used as a pellet ora particle, with a pellet or particle then being formed into a unitarypharmaceutical product, for example, in a capsule, or embedded in atablet, or suspended in a liquid for oral administration.

[0027] Alternatively, in formulating an oral delivery system, each ofthe dosage forms of the product may be formulated as a tablet, with eachof the tablets being put into a capsule to produce a unitary antibioticproduct. Thus, for example, antibiotic products may include a firstdosage form in the form of a tablet that is an immediate release tablet,and may also include two or more additional tablets, each of whichprovides for a delayed release of the antibiotic, as hereinabovedescribed, whereby the C_(max) of the antibiotic released from each ofthe tablets is reached at different times, with the C_(max) of the totalantibiotic released from the antibiotic product being achieved in lessthan twelve hours.

[0028] The formulation of an antibiotic product including at least threedosage forms with different release profiles for different routes ofadministration is deemed to be within the skill of the art from theteachings herein. As known in the art, with respect to delayed release,the time of release can be controlled by the concentration ofantibiotics in the coating and/or the thickness of the coating.

[0029] In formulating an antibiotic product in accordance with theinvention, in one embodiment, the immediate release dosage form of theproduct generally provides from about 20% to about 50% of the totaldosage of antibiotic to be delivered by the product, with such immediaterelease dosage forms generally providing at least 25% of the totaldosage of the antibiotic to be delivered by the product. In many cases,the immediate release dosage form provides from about 20% to about 30%of the total dosage of antibiotic to be delivered by the product;however, in some cases it may be desirable to have the immediate releasedosage form provide for about 45% to about 50% of the total dosage ofantibiotic to be delivered by the product.

[0030] The remaining dosage forms deliver the remainder of theantibiotic. If more than one delayed release dosage form is used, in oneembodiment, each of the delayed release dosage forms may provide aboutequal amounts of antibiotic; however, they may also be formulated so asto provide different amounts.

[0031] In accordance with the present invention, each of the dosageforms contains the same antibiotic; however, each of the dosage formsmay contain more than one antibiotic.

[0032] In one embodiment, where the composition contains one immediaterelease component and two delayed release components, the immediaterelease component provides from 20% to 35% (preferably 20% to 30%), byweight, of the total antibiotic; where there is three delayed releasecomponents, the immediate release component provides from 15% to 30%, byweight, of the total antibiotic; and where there are four delayedrelease components, the immediate release component provides from 10% to25%, by weight, of the total antibiotic.

[0033] With respect to the delayed release components, where there aretwo delayed release components, the first delayed release component (theone released earlier in time) provides from 30% to 60%, by weight, ofthe total antibiotic provided by the two delayed release components withthe second delayed release component providing the remainder of theantibiotic.

[0034] Where there are three delayed release components, the earliestreleased component provides 20% to 35% by weight of the total antibioticprovided by the three delayed release components, the next in timedelayed release component provides from 20% to 40%, by weight, of theantibiotic provided by the three delayed release components and the lastin time providing the remainder of the antibiotic provided by the threedelayed release components.

[0035] When there are four delayed release components, the earliestdelayed release component provides from 15% to 30%, by weight, the nextin time delayed release component provides from 15% to 30%, the next intime delayed release component provides from 20% to 35%, by weight, andthe last in time delayed release component provides from 20% to 35%, byweight, in each case of the total antibiotic provided by the fourdelayed release components.

[0036] The Immediate Release Component

[0037] The immediate release portion of this system can be a mixture ofingredients that breaks down quickly after administration to release theantibiotic. This can take the form of either a discrete pellet orgranule that is mixed in with, or compressed with, the other threecomponents.

[0038] The materials to be added to the antibiotics for the immediaterelease component can be, but are not limited to, microcrystallinecellulose, corn starch, pregelatinized starch, potato starch, ricestarch, sodium carboxymethyl starch, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linkedchitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol,sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose,polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol,Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs(PEG2000-10000) and high molecular weight PEGs (Polyox) with molecularweights above 20,000 daltons.

[0039] It may be useful to have these materials present in the range of1.0 to 60% (W/W).

[0040] In addition, it may be useful to have other ingredients in thissystem to aid in the dissolution of the drug, or the breakdown of thecomponent after ingestion or administration. These ingredients can besurfactants, such as sodium lauryl sulfate, sodium monoglycerate,sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitanmonooleate, glyceryl monostearate, glyceryl monooleate, glycerylmonobutyrate, one of the non-ionic surfactants such as the Pluronic lineof surfactants, or any other material with surface active properties, orany combination of the above.

[0041] These materials may be present in the rate of 0.05-15% (W/W).

[0042] The non-pH Sensitive Delayed Release Component

[0043] The components in this composition are the same immediate releaseunit, but with additional polymers integrated into the composition, oras coatings over the pellet or granule.

[0044] Materials that can be used to obtain a delay in release suitablefor this component of the invention can be, but are not limited to,polyethylene glycol (PEG) with molecular weight above 4,000 daltons(Carbowax, Polyox), waxes such as white wax or bees wax, paraffin,acrylic acid derivatives (Eudragit), propylene glycol, andethylcellulose.

[0045] Typically these materials can be present in the range of 0.5-25%(W/W) of this component.

[0046] The pH Sensitive (Enteric) Release Component

[0047] The components in this composition are the same as the immediaterelease component, but with additional polymers integrated into thecomposition, or as coatings over the pellet or granule.

[0048] The kind of materials useful for this purpose can be, but are notlimited to, cellulose acetate pthalate, Eudragit L, and other pthalatesalts of cellulose derivatives.

[0049] These materials can be present in concentrations from 4-20%(W/W).

[0050] Sustained Release Component

[0051] The components in this composition are the same as the immediaterelease component, but with additional polymers integrated into thecomposition, or as coatings over the pellet or granule.

[0052] The kind of materials useful for this purpose can be, but are notlimited to, ethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose,methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol,or polyethylene glycols with molecular weights in excess of 8,000daltons.

[0053] These materials can be present in concentrations from 4-20%(W/W).

[0054] As hereinabove indicated, the units comprising the antibioticcomposition of the present invention can be in the form of discretepellets or particles contained in the capsule, or particles embedded ina tablet or suspended in a liquid suspension.

[0055] The antibiotic composition of the present invention may beadministered, for example, by any of the following routes ofadministration: sublingual, transmucosal, transdermal, parenteral, etc.,and preferably is administered orally. The composition includes atherapeutically effective amount of the antibiotic, which amount willvary with the antibiotic to be used, the disease or infection to betreated, and the number of times that the composition is to be deliveredin a day. The composition is administered to a host in an amounteffective for treating a bacterial infection.

[0056] This system will be especially useful in extending the practialtherapeutic activity for antibiotics with elimination half lives of lessthan 20 hours and more particularly with elimination half-lives of lessthan 12 hours, and will be particularly useful for those drugs withhalf-lives of 2-10 hours. The following are examples of some antibioticswith half-lives of about 1 to 12 hours: Cefadroxil, cefazolin,cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine,cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone,cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime,ceftriaxone, cefepime, cefinetazole, cefotetan, cefoxitin, loracarbef,imipenem, erythromycin (and erythromycin salts such as estolate,ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin,clarithromycoin, dirithromycin, troleanomycin, penicillin V, penicillinsalts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin,dicloxacillin, amoxicillin, amoxicillin and clavulanate potassium,ampicillin, bacampicillin, carbenicillin indanyl sodium (and other saltsof carbenicillin) mezlocillin, piperacillin, piperacillin andtaxobactam, ticarcillin, ticarcillin and clavulanate potassium,clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin,cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid,ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfioxacin,ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine,sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine,sulfadiazine, sulfinethoxazole, sulfapyridine, metronidazole,methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine,co-triamoxazole, pentamidine, and trimetrexate.

[0057] The invention will be further described with respect to thefollowing examples; however, the scope of the invention is not limitedthereby. All percentages in this specification, unless otherwisespecified, are by weight.

EXAMPLES

[0058] Immediate Release Component

[0059] Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a dry blend. If water or other solvent was used,dry the blend in a suitable pharmaceutical drier, such as a vacuum overor forced-air oven. The product may be sieved or granulated, andcompressed using a suitable tablet press, such as a rotary tablet press.Ingredient Conc. (% W/W) Example 1: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium  5Example 2: Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Povidone10 Croscarmellose sodium 10 Example 3: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellosesodium  5 Example 4: Amoxicillin 75% (W/W) Polyethylene glycol 4000 10Polyethylene glycol 2000 10 Hydroxypropylcellulose  5 Example 5:Amoxicillin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 6: Clarithromycin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 7:Clarithromycin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 8:Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 9: Clarithromycin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 10:Ciprofloxacin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 11:Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 12:Ciprofloxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol2000 10 Hydroxypropylcellulose  5 Example 13: Cirpofloxacin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 14:Ceftibuten 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 15: Ceftibuten 75% (W/W)Polyethylene Glycol 4000 20 Polyvinylpyrrolidone  5

[0060] non-pH Sensitive Delayed Release Component

[0061] Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum over or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press. Ingredient Conc. (% W/W) Example16: Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Polyox 10Croscarmellose sodium  5 Example 17: Amoxicillin 55% (W/W)Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example18: Amoxicillin 65% (W/W) Polyox 20 Hydroxypropylcellulose 10Croscarmellose sodium  5 Example 19: Amoxicillin 75% (W/W) Polyethyleneglycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D  5 Example20: Amoxicillin 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose  5Example 21: Clarithromycin 70% (W/W) Polyox 20 Hydroxypropylcellulose  5Croscarmellose sodium  5 Example 22: Clarithromycin 75% (W/W) Polyox 15Hydroxypropylcellulose  5 Ethylcellulose  5 Example 23: Clarithromycin75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10Eudragit RL 30D  5 Example 24: Clarithromycin 80% (W/W) Polyethyleneglycol 8000 10 Polyvinylpyrrolidone  5 Eudgragit R 30D  5 Example 25:Ciprofloxacin 65% (W/W) Polyethylene glycol 4000 20Hydroxypropylcellulose 10 Eudragit RL 30D  5 Example 26: Ciprofloxacin75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose  5Ethylcellulose  5 Example 27: Ciprofloxacin 80% (W/W) Polyethyleneglycol 4000 10 Polyethylene glycol 2000  5 Eudgragit RL 30D  5 Example28: Ciprofloxacin 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5 Example 29: Ceftibuten 75% (W/W) Polyethylene glycol 4000 10Polyethylene glycol 2000 10 Eudragit RL 30D  5 Example 30: Ceftibuten75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose  5

[0062] Enteric Release Component

[0063] Formulate the ingredients by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum over or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press. Ingredient Conc. (% W/W) Example31: Amoxicillin 65% (W/W) Microcrystalline cellulose 20 CelluloseAcetate Pthalate 15 Example 32: Amoxicillin 55% (W/W) Microcrystallinecellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose10 Example 33: Amoxicillin 65% (W/W) Polyox 20 Hydroxypropylcellulosepthalate 10 Eudragit L30D  5 Example 34: Amoxicillin 75% (W/W)Polyethylene glycol 2000 10 Eudragit L30D 10 Eudragit RL 30D  5 Example35: Amoxicillin 40% (W/W) Microcrystalline Cellulose 40 CelluloseAcetate Pthalate 10 Example 36: Clarithromycin 70% (W/W)Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 37:Clarithromycin 70% (W/W) Eudragit E30D 15 Hydroxypropylcellulose 10Ethylcellulose  5 Example 38: Clarithromycin 75% (W/W) Polyethyleneglycol 2000 10 Eudragit E 30D 15 Example 39: Clarithromycin 40% (W/W)Lactose 50 Eudgragit L 30D 10 Example 40: Ciprofloxacin 65% (W/W)Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 41:Ciprofloxacin 75% (W/W) Microcrystalline Cellulose 15Hydroxypropylcellulose pthalate 10 Example 42: Ciprofloxacin 80% (W/W)Lactose 10 Eudgragit L 30D 10 Example 43: Ciprofloxacin 70% (W/W)Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example 44:Ceftibuten 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 Eudragit L30D 10 Example 45: Ceftibuten 70% (W/W) Microcrystalline cellulose 20Cellulose acetate pthalate 10

[0064] Sustained Release Component

[0065] Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum over or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press. Ingredient Conc. (% W/W) Example46: Amoxicillin 65% (W/W) Ethylcellulose 20 Polyox 10Hydroxypropylmethylcellulose  5 Example 47: Amoxicillin 55% (W/W)Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 48: Amoxicillin 70%(W/W) Polyox 20 Hydroxypropylcellulose 10 Example 49: Clarithromycin 75%(W/W) Lactose 15 Hydroxypropylcellulose  5 Ethylcellulose  5 Example 50:Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Lactose 10 EudragitRL 30D  5 Example 51: Clarithromycin 80% (W/W) Polyethylene glycol 800010 Hydroxypropylmethylcellulose  5 Eudgragit RS 30D  5 Example 52:Ciprofloxacin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol4000 10 Hydroxypropylcellulose  5 Example 53: Ciprofloxacin 75% (W/W)Lactose 10 Povidone (PVP) 10 Polyethylene glycol 2000  5 Example 54:Ceftibuten 75% (W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10Hydroxypropylcellulose  5 Example 55: Ceftibuten 75% (W/W) Lactose 15Polyethylene glycol 4000  5 Polyvinylpyrrolidone  5

[0066] Three Pulses

Example 56.

[0067] 1. Metronidazole Matrix Pellet Formulation and PreparationProcedure (Immediate Release)

[0068] A. Pellet Formulation

[0069] The composition of the metronidazole matrix pellets provided inTable 1. TABLE 1 Composition of Metronidazole Pellets ComponentPercentage (%) Metronidazole 50 Avicel PH 101 20 Lactose 20 PVP K29/32*10 Purified Water Total 100

[0070] B. Preparation Procedure for Metronidazole Matrix Pellets

[0071] 1.2.1 Blend metronidazole and Avicel® PH101 using a Robot Coupehigh shear granulator.

[0072] 1.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0073] 1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0074] 1.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0075] 1.2.5 Dry the spheronized pellets at 50° C. overnight.

[0076] 1.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0077] 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0078] A. Dispersion Formulation

[0079] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the metronidazole matrix pellets is provided below in Table2. TABLE 2 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0080] B. Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0081] 1.3.1 Suspend triethyl citrate and talc in deionized water.

[0082] 1.3.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0083] 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0084] 1.3.4 Allow the coating dispersion to stir for one hour prior toapplication onto the metronidazole matrix pellets.

[0085] 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0086] A. Dispersion Formulation

[0087] The composition of the aqueous Eudragit® S 100 dispersion appliedto the metronidazole matrix pellets is provided below in Table 3. TABLE3 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0088] B. Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0089] Part I:

[0090] (i) Dispense Eudragit® S 100 powder in deionized water withstirring.

[0091] (ii) Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0092] (iii) Allow the partially neutralized dispersion to stir for 60minutes.

[0093] (iv) Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0094] Part II:

[0095] (i) Disperse talc in the required amount of water

[0096] (ii) Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0097] (iii) Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0098] 1.5 Coating Conditions for the Application of Aqueous CoatingDispersions

[0099] The following coating parameters were used to coat matrix pelletswith each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous filmcoating. Coating Equipment STREA 1 ™ Table Top Laboratory Fluid BedCoater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet AirTemperature 40 to 45° C. Outlet Air Temperature 30 to 33° C. AtomizationAir Pressure 1.8 Bar Pump Rate 2 gram per minute

[0100] (i) Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0101] (ii) Coat matrix pellets with S100 dispersion such that you apply20% coat weight gain to the pellets.

[0102] 1.6 Encapsulation of the Metronidazole Pellets

[0103] Pellets are filled into size 00 hard gelatin capsules at a ratioof 30%: 30%: 40%:

[0104] Immediate-release matrix pellets uncoated, L30 D-55 coatedpellets and S100 coated pellets respectively.

[0105] The capsule is filled with the three different pellets to achievea total dose of 375 mg/capsule.

[0106] Three Pulses

Example 57

[0107] Amoxicillin Pellet Formulation and Preparation Procedure

[0108] 57.1 Pellet Formulations for Subsequent Coating

[0109] The composition of the Amoxicillin trihydrate matrix pelletsprovided in Table 4. TABLE 4 Composition of Amoxicillin Matrix PelletsComponent Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0110] 57.2 Preparation Procedure for Amoxicillin Matrix Pellets

[0111] 57.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shearblender.

[0112] 57.2.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0113] 57.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator is 0.8 mm.

[0114] 57.2.4 Spheronize the extrudate using a QJ-230 Spheronizer usinga small cross section plate.

[0115] 57.2.5 Dry the spheronized pellets at 60° C. using a fluid beddryer until the exhaust temperature reaches 40° C.

[0116] 57.2.6 Pellets between 20 and 40 Mesh were collected for furtherprocessing.

[0117] 57.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0118] 57.3.1 Dispersion Formulation

[0119] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the amoxicillin matrix pellets is provided below in Table 5.TABLE 5 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5

[0120] 57.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0121] 57.4.1 Suspend triethyl citrate and talc in deionized water.

[0122] 57.4.2 The TEC/talc suspension is mixed using laboratory mixer.

[0123] 57.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L30 D-55 latex dispersion while stirring.

[0124] 57.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the amoxicillin matrix pellets.

[0125] 57.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0126] 57.5.1 Dispersion Formulation

[0127] The composition of the aqueous Eudragit® S 100 dispersion appliedto the Amoxicillin matrix pellets is provided below in Table 6. TABLE 6Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content 25.0 PolymerContent 10.0

[0128] 57.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0129] Part A:

[0130] 57.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0131] 57.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0132] 57.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0133] 57.6.4 Add triethyl citrate drop-wise into the dispersion withstirring and let stir overnight prior to the addition of Part B.

[0134] Part B:

[0135] 57.6.5 Disperse talc in the required amount of water

[0136] 57.6.6 Stir the dispersion using an overhead laboratory mixer.

[0137] 57.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0138] 57.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0139] The following coating parameters were used for both the Eudragit®L 30 D-55 and Eudragit®S 100 aqueous film coating processes. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45°C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure 1.8 BarPump Rate 2-6 gram per minute

[0140] 57.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 20% coat weight gain to the pellets.

[0141] 57.7.2 Coat matrix pellets with S100 dispersion such that youapply 37% coat weight gain to the pellets.

[0142] 57.8 Preparation of Amoxicillin Granulation (Immediate ReleaseComponent) for Tabletting TABLE 7 Composition of Amoxicillin GranulationComponent Percentage (%) Amoxicillin Trihydrate powder 92   Avicel PH101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100   

[0143] 57.8.1 Blend Amoxicillin and Avicel® PH 101 using a low shearblender.

[0144] 57.8.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0145] 57.8.3 Dry the granulation at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

[0146] 57.8.4 Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0147] 57.9 Tabletting of the Amoxicillin Pellets TABLE 8 Composition ofAmoxicillin Tablets Component Percentage (%) Amoxicillin granules 32.5Avicel PH 200 5.0 Amoxicillin L30D-55 coated pellets 30 Amoxicillin S100coated pellets 30 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0Total 100

[0148] 57.9.1 Blend the Amoxicillin granules, Avicel PH-200 ,Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in atumble blender.

[0149] 57.9.2 Add the magnesium stearate to the blender, and blend for 5minutes.

[0150] 57.9.3 Compress the blend on a rotary tablet press.

[0151] 57.9.4 The fill weight should be adjusted to achieve a 500 mgdose tablet.

[0152] Three Pulses

Example 58

[0153] Clarithromycin Pellet Formulation and Preparation Procedure

[0154] 58.1 Pellet Formulation

[0155] The composition of the clarithromycin matrix pellets provided inTable 1. TABLE 9 Composition of Clarithromycin Pellets ComponentPercentage (%) Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1Silicified microcrystalline cellulose 14.6 Polyoxyl 35 Castor Oil* 1.7Hydroxypropyl methylcellulose* 1.0 Total 100

[0156] 58.2 Preparation Procedure for Clarithromycin Matrix Pellets

[0157] 58.2.1 Blend clarithromycin, silicified microcrystallinecellulose and lactose monohydrate using a Robot Coupe high sheargranulator.

[0158] 58.2.2 Prepare the binder solution by adding the Polyoxyl to thepurified water while stirring. After that is mixed, slowly add thehydroxypropyl methylcellulose and continue to stir until a solution isachieved.

[0159] 58.2.3 Add binder solution slowly into the powder blend undercontinuous mixing.

[0160] 58.2.4 Granulate the powders in the high shear granulator withthe binder solution.

[0161] 58.2.5 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator was 1.2 mm.

[0162] 58.2.6 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0163] 58.2.7 Dry the spheronized pellets at 50° C. overnight.

[0164] 58.2.8 Pellets between 18 and 30 Mesh were collected for furtherprocessing.

[0165] 58.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0166] 58.3.1 Dispersion Formulation

[0167] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the clarithromycin matrix pellets is provided below in Table10. TABLE 10 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1Water 51.7 Solids Content 20.0 Polymer Content 12.1

[0168] 58.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0169] 58.4.1 Suspend triethyl citrate and talc in deionized water.

[0170] 58.4.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0171] 58.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0172] 58.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the clarithromycin matrix pellets.

[0173] 58.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0174] 58.5.1 Dispersion Formulation

[0175] The composition of the aqueous Eudragit® S 100 dispersion appliedto the clarithromycin matrix pellets is provided below in Table 11.TABLE 11 Eudragit ® S 100 Aqueous Coating Dispersion ComponentPercentage (%) Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content25.0 Polymer Content 10.0

[0176] 58.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0177] Part A:

[0178] 58.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0179] 58.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0180] 58.6.3 Allow the partially neutralized dispersion to stir for 60minutes

[0181] 58.6.4 Add the triethyl citrate drop-wise to the dispersion andstir for 60 minutes prior to the addition of Part B.

[0182] Part B:

[0183] 58.6.5 Disperse talc in the required amount of water

[0184] 58.6.6 Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0185] 58.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0186] 58.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0187] The following coating parameters were used for coating the matrixpellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueousfilm coating. Coating Equipment STREA 1 ™ Table Top Laboratory Fluid BedCoater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet AirTemperature 40 to 45° C. Outlet Air Temperature 30 to 33° C. AtomizationAir Pressure 1.6 Bar Pump Rate 2 gram per minute

[0188] 58.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 20% coat weight gain to the pellets.

[0189] 58.7.2 Coat matrix pellets with S100 dispersion such that youapply 37% coat weight gain to the pellets.

[0190] 4. Capsules were filled with the uncoated pellets, the L30D-55coated pellets and S100 coated pellets in weight percentages of30%:30%:40%, respectively to provide 250 mg. capsules.

[0191] Four pulses

Example 59.

[0192] 1 Metronidazole Matrix Pellet Formulation and PreparationProcedure

[0193] 59.1 Pellet Formulation

[0194] The composition of the metronidazole matrix pellets provided inTable 12. TABLE 12 Composition of Metronidazole Pellets ComponentPercentage (%) Metronidazole 50 Avicel PH 101 20 Lactose 20 PVP K29/32*10 Purified Water Total 100

[0195] 59.2 Preparation Procedure for Metronidazole Matrix Pellets

[0196] 59.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupehigh shear granulator.

[0197] 59.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0198] 59.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0199] 59.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0200] 59.2.5 Dry the spheronized pellets at 50° C. overnight.

[0201] 59.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0202] 59.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0203] 59.3.1 Dispersion Formulation

[0204] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the metronidazole matrix pellets is provided below in Table13. TABLE 13 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0205] 59.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0206] 59.4.1 Suspend triethyl citrate and talc in deionized water.

[0207] 59.4.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0208] 59.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0209] 59.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the metronidazole matrix pellets.

[0210] 59.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0211] 59.5.1 Dispersion Formulation

[0212] The composition of the aqueous Eudragit® S 100 dispersion appliedto the metronidazole matrix pellets is provided below in Table 14. TABLE14 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0213] 59.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0214] Part A:

[0215] 59.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0216] 59.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0217] 59.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0218] 59.6.4 Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0219] Part B:

[0220] 59.6.5 Disperse talc in the required amount of water

[0221] 59.6.6 Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0222] 59.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0223] 59.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0224] The following coating parameters were used for coating with eachof the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2 gram per minute

[0225] 59.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0226] 59.7.2 Coat matrix pellets with L30 D-55 dispersion such that youapply 30% coat weight gain to the pellets.

[0227] 59.7.3 Coat matrix pellets with S100 dispersion such that youapply 20% coat weight gain to the pellets.

[0228] 59.8 Encapsulation of the Metronidazole Pellets

[0229] Pellets are filled into size 00 hard gelatin capsules at a ratioof 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weightgain and S 100 coated pellets respectively. The capsule is filled withthe four different pellets to achieve a total dose of 375 mg/capsule.

[0230] Four Pulses

Example 60

[0231] Amoxicillin Pellet Formulation and Preparation Procedure

[0232] 60.1 Pellet Formulations

[0233] The composition of the Amoxicillin trihydrate matrix pelletsprovided in Table 15. TABLE 15 Composition of Amoxicillin Matrix PelletsComponent Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0234] 60.2 Preparation Procedure for Amoxicillin Matrix Pellets

[0235] 60.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shearblender.

[0236] 60.2.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0237] 60.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator is 0.8 mm.

[0238] 60.2.4 Spheronize the extrudate using a QJ-230 Spheronizer usinga small cross section plate.

[0239] 60.2.5 Dry the spheronized pellets at 60° C. using a fluid beddryer until the exhaust temperature reaches 40° C.

[0240] 60.2.6 Pellets between 20 and 40 Mesh were collected for furtherprocessing.

[0241] 60.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0242] 60.3.1 Dispersion Formulation

[0243] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the amoxicillin matrix pellets is provided below in Table 16.TABLE 16 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5

[0244] 60.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0245] 60.4.1 Suspend triethyl citrate and talc in deionized water.

[0246] 60.4.2 The TEC/talc suspension is mixed using laboratory mixer.

[0247] 60.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L30 D-55 latex dispersion while stirring.

[0248] 60.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the amoxicillin matrix pellets.

[0249] 60.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0250] 60.6 Dispersion Formulation

[0251] The composition of the aqueous Eudragit® S 100 dispersion appliedto the Amoxicillin matrix pellets is provided below in Table 17. TABLE17 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate5.0 Water 64.9 Part B Talc 2.0 Water 10.0 Solid Content 25.0 PolymerContent 10.0

[0252] 60.7 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0253] Part A:

[0254] 60.7.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0255] 60.7.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0256] 60.7.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0257] 60.7.4 Add triethyl citrate drop-wise into the dispersion withstirring and let stir overnight prior to the addition of Part B.

[0258] Part B:

[0259] 60.7.5 Disperse talc in the required amount of water

[0260] 60.7.6 Stir the dispersion using an overhead laboratory mixer.

[0261] 60.7.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0262] 60.8 Preparation of Aquacoat Coating Dispersion

[0263] 60.8.1 Dispersion Formulation

[0264] The composition of the aqueous Aquacoat dispersion applied toAmoxicillin L30 D-55 coated pellets is provided below in Table 18. TABLE18 Component Percentage (%) Aquacoat ECD 79.3 Hydroxypropylmethylcellulose 15.9 Dibutyl Sebacate 4.8 Purified Water (300 g)

[0265] 60.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel E15)solution by dispersing in water with continuous stirring.

[0266] 60.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion withstirring and continue to stir overnight.

[0267] 60.9 Coating Conditions for the Application of Aqueous CoatingDispersions

[0268] The following coating parameters were used for coating with eachof the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2-6 gram per minute

[0269] 60.9.1 Coat Amoxicillin matrix pellets with L30 D-55 dispersim toachieve a 20% coat weight gain.

[0270] 60.9.2 Coat another batch of Amoxicillin matrix pellets with L30D-55 dispersion to achieve a 20% weight gain. Coat the L30 D-55 pelletswith the Aquacoat Dispersion to achieve a 10% coat weight gain.

[0271] 60.9.3 Coat Amoxicillin matrix pellets with S100 dispersion toachieve a 37% coat weight gain.

[0272] 60.10 Preparation of Amoxicillin Granulation for tabletting TABLE19 Composition of Amoxicillin Granulation (Immediate Release) ComponentPercentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0273] 60.10.1 Blend Amoxicillin and Avicel® PH 101 using a low shearblender.

[0274] 60.10.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0275] 60.10.3 Dry the granulation at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

[0276] 60.10.4 Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0277] 60.11 Tabletting of the Amoxicillin Pellets TABLE 20 Compositionof Amoxicillin Tablets Component Percentage (%) Amoxicillin granules32.5 Avicel PH 200 5.0 Amoxicillin L30D-55 coated pellets 20 AmoxicillinAquacoated pellets 20 Amoxicillin S100 coated pellets 20 Colloidalsilicon dioxide 1.5 Magnesium stearate 1.0 Total 100

[0278] 60.11.1 Blend the Amoxicillin granules, Avicel PH-200,Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in atumble blender.

[0279] 60.11.2 Add the magnesium stearate to the blender, and blend for5 minutes.

[0280] 60.11.3 Compress the blend on a rotary tablet press.

[0281] 60.11.4 The fill weight should be adjusted to achieve a 500 mgdose tablet.

[0282] Four Pulses

Example 61

[0283] Clarithromycin Pellet Formulation and Preparation Procedure

[0284] 61.1 Pellet Formulation

[0285] The composition of the clarithromycin matrix pellets provided inTable 21. TABLE 21 Composition of Clarithromycin Pellets ComponentPercentage (%) Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1Silicified microcrystalline cellulose 14.6 Polyoxyl 35 Castor Oil* 1.7Hydroxypropyl methylcellulose* 1.0 Total 100

[0286] 61.2 Preparation Procedure for Clarithromycin Matrix Pellets

[0287] 61.2.1 Blend clarithromycin, silicified microcrystallinecellulose and lactose monohydrate using a Robot Coupe high sheargranulator.

[0288] 61.2.2 Prepare the binder solution by adding the Polyoxyl to thepurified water while stirring. After that is mixed, slowly add thehydroxypropyl methylcellulose and continue to stir until a solution isachieved.

[0289] 61.2.3 Add binder solution slowly into the powder blend undercontinuous mixing.

[0290] 61.2.4 Granulate the powders in the high shear granulator withthe binder solution.

[0291] 61.2.5 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator was 1.2 mm.

[0292] 61.2.6 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0293] 61.2.7 Dry the spheronized pellets at 50° C. overnight.

[0294] 61.2.8 Pellets between 18 and 30 Mesh were collected for furtherprocessing.

[0295] 61.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0296] 61.3.1 Dispersion Formulation

[0297] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the clarithromycin matrix pellets is provided below in Table22. TABLE 22 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1Water 51.7 Solids Content 20.0 Polymer Content 12.1

[0298] 61.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0299] 61.4.1 Suspend triethyl citrate and talc in deionized water.

[0300] 61.4.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0301] 61.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0302] 61.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the clarithromycin matrix pellets.

[0303] 61.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0304] 61.5.1 Dispersion Formulation

[0305] The composition of the aqueous Eudragit® S 100 dispersion appliedto the clarithromycin matrix pellets is provided below in Table 23.TABLE 23 Eudragit ® S 100 Aqueous Coating Dispersion ComponentPercentage (%) Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content25.0 Polymer Content 10.0

[0306] 61.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0307] Part A:

[0308] 61.6.1 Dispense Eudragit® S100 powder in deionized water withstirring.

[0309] 61.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0310] 61.6.3 Allow the partially neutralized dispersion to stir for 60minutes

[0311] 61.6.4 Add the triethyl citrate drop-wise to the dispersion andstir for 60 minutes prior to the addition of Part B.

[0312] Part B:

[0313] 61.6.5 Disperse talc in the required amount of water

[0314] 61.6.6 Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0315] 61.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0316] 61.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0317] The following coating parameters were used for coating with eachof the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.STREA Coating Equipment 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.6 Bar Pump Rate 2 gram per minute

[0318] 61.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0319] 61.7.2 Coat matrix pellets with L30 D-55 dispersion such that youapply 30% coat weight gain to the pellets.

[0320] 61.7.3 Coat matrix pellets with S100 dispersion such that youapply 37% coat weight gain to the pellets.

[0321] 61.8 Encapsulation of the Clarithromycin Pellets

[0322] Pellets are filled into size 00 hard gelatin capsules at a ratioof 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weightgain and S100 coated pellets respectively.

[0323] The capsule is filled with the four different pellets to achievea total dose of 250 mg/capsule.

[0324] Four Pulses

Example 62

[0325] Clarithromycin Pellet Formulation and Preparation Procedure

[0326] Pellet Formulation

[0327] The composition of the clarithromycin pellets provided inTable 1. TABLE 1 Composition of Clarithromycin Pellets ComponentPercentage (%) Clarithromycin 77.0 Lactose monohydrate, spray dried 11.0Croscarmellose sodium 5.0 Polyoxyl 35 Castor Oil* 5.0 Hydroxypropylmethylcellulose* 2.0 Purified water * Total 100

[0328] Preparation Procedure for Clarithromycin Pellets

[0329] Prepare the binder solution by adding the Polyoxyl to thepurified water while stirring. After that is mixed, slowly add thehydroxypropyl methylcellulose and continue to stir until a solution isachieved.

[0330] Blend clarithromycin, lactose monohydrate, and croscarmellosesodium using a Robot Coupe high shear granulator.

[0331] Add binder solution slowly into the powder blend under continuousmixing.

[0332] Granulate the powders in the high shear granulator with thebinder solution.

[0333] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0334] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0335] Dry the spheronized pellets at 50° C. until the moisture level is>3%.

[0336] Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0337] Clarithromycin Enteric-Release Pellet Formulation and PreparationProcedure

[0338] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D AqueousCoating Dispersion

[0339] Dispersion Formulation

[0340] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30Daqueous coating dispersion applied to the clarithromycin pellets isprovided below in Table 2. TABLE 2 Eudragit ® L 30 D-55/Eudragit NE 30DAqueous Coating Dispersion Component Percentage (%) Eudragit ® L 30D-5544.4 Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9 PurifiedWater* 38.6 Solid Content 20.6 Polymer Content 16.4

[0341] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30DAqueous Dispersion

[0342] Heat purified water to 75-80° C. and then add triethyl citrate(TEC) and Imwitor 900. Homogenize dispersion until temperature is lessthan 55° C.

[0343] The TEC/Imwitor 900 dispersion is then stirred until thetemperature is less than 35° C.

[0344] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latexdispersion and stir for at least 30 minutes.

[0345] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900dispersion and stir for at least 10 minutes.

[0346] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0347] Continue to stir the dispersion until the coating process iscomplete.

[0348] Coating Conditions for the Application of EudragitL30D-55/Eudragit NE 30D Aqueous

[0349] Coating Dispersion

[0350] The following coating parameters were used for coating of theEudragit® L 30 D-55/Eudragit NE30D film coating dispersion. STREACoating Equipment 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 45° C.Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

[0351] Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE30D film coating dispersion such that you apply 20% coat weight gain tothe pellets.

[0352] Clarithromycin Delayed Enteric-Release Pellets Formulation andPreparation Procedure

[0353] Preparation of an AQOAT AS-HF Aqueous Coating Dispersion

[0354] Dispersion Formulation

[0355] The composition of the aqueous AQOAT AS-HF aqueous coatingdispersion applied to the clarithromycin pellets is provided below inTable 3. TABLE 3 AQOAT AS-HF Aqueous Coating Dispersion ComponentPercentage (%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodiumlauryl sulfate 0.2 Purified Water* 88.7 Solid Content 11.3 PolymerContent 7.0

[0356] Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion

[0357] Add triethyl citrate (TEC) to the purified water with stirring.

[0358] Add the sodium lauryl sulfate (SLS) to the TEC dispersion withstirring and completely until completely dissolved.

[0359] Add the AQOAT to the TEC/SLS dispersion and stir for at least 30minutes.

[0360] Add the talc to the AQOAT dispersion and until completely mixedand for at least 30 minutes.

[0361] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0362] Continue to stir the dispersion until the coating process iscomplete.

[0363] Coating Conditions for the Application of AQOAT AS-HF AqueousCoating Dispersion

[0364] The following coating parameters were used for coating of theAQOAT AS-HF film coating dispersion. STREA Coating Equipment 1 ™ TableTop Laboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm MaterialCharge 300 gram Inlet Air Temperature 48° C. Outlet Air Temperature 27°C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute

[0365] Coat clarithromycin pellets with AQOAT AS-HF film coatingdispersion such that you apply 30-35% coat weight gain to the pellets.

[0366] Clarithromycin Colonic-Release Pellets Formulation andPreparation Procedure

[0367] Preparation of an Eudragit® FS30D Aqueous Coating Dispersion

[0368] Dispersion Formulation

[0369] The composition of the aqueous Eudragit® FS 30D dispersionapplied to the clarithromycin pellets is provided below in Table 4.TABLE 4 Eudragit ® FS 30D Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4

[0370] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0371] Disperse triethyl citrate (TEC) in the purified water.

[0372] Add the talc in the triethyl citrate dispersion.

[0373] Homogenize the dispersion using a homogenizer.

[0374] Add slowly the Eudragit® FS 30D dispersion to the talc/TECdispersion with stirring.

[0375] Continue to stir the coating dispersion until the coating processis complete.

[0376] Coating Conditions for the Application of Eudragit FS30D AqueousCoating Dispersion

[0377] The following coating parameters were used for coating with eachof the Eudragit® FS 30 D aqueous film coating. STREA Coating Equipment1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.2 mmMaterial Charge 300 gram Inlet Air Temperature 38° C. Outlet AirTemperature 22° C. Atomization Air Pressure 1.6 Bar Pump Rate 6 gram perminute

[0378] Coat pellets with Eudragit FS 30D coating dispersion dispersionsuch that you apply 30% coat weight gain to the pellets.

[0379] Encapsulation of the Clarithromycin Pellets

[0380] Pellets are filled into hard gelatin capsules at a ratio of 25%:25%: 25%: 25% Immediate-Release Pellets (uncoated), Eudragit L30D-55/Eudagit NE 30D coated pellets 20% weight gain, AQOAT AS-HF coatedpellets 30-35% weight gain and Eudragit FS 30D coated pelletsrespectively.

[0381] The capsule is filled with the four different pellets to achievea total dose of 250 mg/capsule.

[0382] Tableting of the Clarithromycin Pellets

[0383] Clarithromycin Tablet Formula TABLE 5 Clarithromycin TabletComponent Percentage (%) Eudragit ® L30D/NE 30D coated pellets 20.0AQOAT AS-HF coated pellets 20.0 Eudargit FS 30D coated pellets 20.0Emcocel 24.5 Clarithromycin 12.5 Povidone K30 2.0 Magnesium stearate 1.0Purified water *

[0384] Preparation Procedure for a Clarithromycin Tablet

[0385] Blend all the components together except coated pellets andmagnesium stearate for 10 minutes using a granulator.

[0386] Granulate the blend with purified water.

[0387] Screen the granulate through a No. 16 mesh sieve.

[0388] Dry the screened granulate in a fluid bed dryer at 50-60° C.until the moisture level is less than 3%.

[0389] Add the dry granulate, coated pellets to a tumble blender andblend for 10 minutes.

[0390] Add to the blend the magnesium stearate and blend an additional 3minutes.

[0391] Compress the blend on a rotary tablet press to achieve a dose of500 mg.

[0392] The present invention is particularly advantageous in that thereis provided an antibiotic product which provides an improvement overtwice a day administration of the antibiotic and an improvement over aonce a day administration of the antibiotic.

[0393] Numerous modification and variations of the present invention arepossible in light of the above teachings and therefore, within the scopeof the appended claims the invention may be practiced otherwise than asparticularly described.

[0394] The present invention is particularly advantageous in that thereis provided an antibiotic product which provides an improvement overtwice a day administration of the antibiotic and an improvement over aonce a day administration of the antibiotic.

[0395] Numerous modification and variations of the present invention arepossible in light of the above teachings and therefore, within the scopeof the appended claims the invention may be practiced otherwise than asparticularly described.

What is claimed is:
 1. An antibiotic product comprising: a firstantibiotic dosage form, a second antibiotic dosage form, and a thirdantibiotic dosage form, each of said first, second and third antibioticdosage forms comprising an antibiotic and a pharmaceutically acceptablecarrier, said three dosage forms having different release profiles, saidantibiotic product reaching a C_(max) in less than about twelve hourswherein the antibiotic is an erythromyacin.
 2. The product of claim 1wherein the first dosage form is an immediate release dosage form. 3.The product of claim 2 wherein the C_(max) for the product is reached noearlier than four hours after administration.
 4. The product of claim 2wherein the immediate release dosage form contains at least 20% and nomore than 50% of the total dosage of antibiotic.
 5. The product of claim4 wherein the product is an oral dosage form.
 6. The product of claim 5wherein the antibiotic released from the second dosage in the formreaches a C_(max) in the serum after C_(max) is reached in the serum forantibiotic released from the first dosage form.
 7. The product of claim6 wherein the antibiotic released from the third dosage form reaches aC_(max) in the serum after the antibiotic released from the seconddosage form reaches a C_(max) in the serum.
 8. The antibiotic product ofclaim 1 wherein said antibiotic product includes a total dosage ofantibiotic that is effective for a twenty four hour period.
 9. Theproduct of claim 1 and further comprising a fourth antibiotic dosageform comprising an antibiotic and a pharmaceutically acceptable carrier,wherein antibiotic released from the fourth dosage form reaches aC_(max) in the serum after C_(max) is achieved in the serum forantibiotic released from each of the first, second and third dosageforms.
 10. A process for treating a bacterial infection in a hostcomprising: administering to a host the antibiotic product of claim 1.11. A process for treating a bacterial infection in a host comprising:administering to a host the antibiotic product of claim
 2. 12. A processfor treating a bacterial infection in a host comprising: administeringto a host the antibiotic product of claim
 3. 13. A process for treatinga bacterial infection in a host comprising: administering to a host theantibiotic product of claim
 4. 14. A process for treating a bacterialinfection in a host comprising: administering to a host the antibioticproduct of claim
 5. 15. A process for treating a bacterial infection ina host comprising: administering to a host the antibiotic product ofclaim
 6. 16. A process for treating a bacterial infection in a hostcomprising: administering to a host the antibiotic product of claim 7.17. A process for treating a bacterial infection in a host comprising:administering to a host the antibiotic product of claim
 8. 18. A processfor treating a bacterial infection in a host comprising: administeringto a host the antibiotic product of claim
 9. 19. An antibiotic productcomprising: a first antibiotic dosage form, a second antibiotic dosageform, and a third antibiotic dosage form, each of said first, second andthird antibiotic dosage forms comprising an antibiotic and apharmaceutically acceptable carrier, said three dosage forms havingdifferent release profiles, said antibiotic product reaching a C_(max)in less than about twelve hours, wherein the antibiotic is anerythromyacin, said first dosage form being an immediate release dosageform, said second and third dosage forms, each being a delayed releasedosage form, wherein the antibiotic released from the first dosage formreaches a C_(max) in serum in from 0.5 to 2 hours after administrationof the product, wherein the antibiotic released from the second dosageform reaches a C_(max) in serum in no more than 4 hours afteradministration of the product and after C_(max) is reached forantibiotic from the first dosage form and the antibiotic released fromthe third dosage form reaches a C_(max) in serum within 8 hours, andafter the C_(max) is reached for the antibiotic released from the seconddosage form.
 20. The product of claim 19 wherein the second dosage forminitiates release of the antibiotic at least one hour after the firstdosage form.
 21. The product of claim 20 wherein the C_(max) for thesecond dosage form is reached no earlier than two hours after productadministration.
 22. The product of claim 21 wherein the first dosageform contains from about 20% to about 50%, by weight, of the totalantibiotic of the product, wherein the second dosage form contains from30% to 60%, by weight, of the antibiotic that is contained in the secondand third dosage forms.
 23. The product of claim 22 wherein the firstdosage form contains from 15% to 30%, by weight, of the total antibioticpresent in the product.
 24. The product of claim 22 wherein the productincludes a fourth delayed release antibiotic dosage form having adifferent release profile from the first, second and third dosage forms.25. The product of claim 24 wherein the second dosage form contains from20% to 35%, by weight, of the total antibiotic present in the second,third and fourth dosage forms, the third dosage form contains from 20%to 40%, by weight, of the total antibiotic present in the second, thirdand fourth dosage forms, with the remainder being present in the fourthdosage form.
 26. The product of claim 19 wherein C_(max) for the productis reached no earlier than four hours after administration.
 27. Theproduct of claim 1 wherein the antibiotic is Clarithromycin.